TY - JOUR T1 - Development of Remdesivir as a Dry Powder for Inhalation by Thin Film Freezing JF - bioRxiv DO - 10.1101/2020.07.26.222109 SP - 2020.07.26.222109 AU - Sawittree Sahakijpijarn AU - Chaeho Moon AU - John J. Koleng AU - Dale J. Christensen AU - Robert O. Williams III Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/09/22/2020.07.26.222109.abstract N2 - Remdesivir exhibits in vitro activity against SARS-CoV-2 and was granted approval for Emergency Use. To maximize delivery to the lungs, we formulated remdesivir as a dry powder for inhalation using thin film freezing (TFF). TFF produces brittle matrix nanostructured aggregates that are sheared into respirable low-density microparticles upon aerosolization from a passive dry powder inhaler. In vitro aerodynamic testing demonstrated that drug loading and excipient type affected the aerosol performance of remdesivir. Remdesivir combined with optimal excipients exhibited desirable aerosol performance (up to 93.0% FPF; 0.82μm MMAD). Remdesivir was amorphous after the TFF process, which benefitted drug dissolution in simulated lung fluid. TFF remdesivir formulations are stable after one-month storage at 25 °C/60%RH. In vivo pharmacokinetic evaluation showed that TFF-remdesivir-leucine was poorly absorbed into systemic circulation while TFF-remdesivir-Captisol® demonstrated increased systemic uptake compared to leucine. Remdesivir was hydrolyzed to the nucleoside analog GS-441524 in lung, and levels of GS-441524 were greater in lung with the leucine formulation compared to Captisol®. In conclusion, TFF technology produces high potency remdesivir dry powder formulations for inhalation suitable to treat patients with COVID-19 on an outpatient basis and earlier in the disease course where effective antiviral therapy can reduce related morbidity and mortality.Competing Interest StatementThis research was funded by TFF Pharmaceuticals, Inc. through a sponsored research agreement at The University of Texas at Austin. All authors are co-inventors on related intellectual property. The Board of Regents of The University of Texas has licensed IP covering inhaled remdesivir formulations prepared with thin film freezing to TFF Pharmaceuticals, Inc. Moon and Sahakijpijarn acknowledge consulting for TFF Pharmaceuticals, Inc. Williams acknowledges ownership of stock in TFF Pharmaceuticals, Inc. ER -